Platinum based agents (Pt) are the most commonly prescribed chemotherapeutics used in the treatment of solid tumors and are part of the curative treatment regimen for testicular cancer. While front line Pt therapy for lung cancer is often initially effective, resistance to Pt contributes to this disease remaining the most deadly cancer in both men and women, claiming more lives than the next four cancer types combined. Similarly, epithelial ovarian cancer (EOC) is uniformly fatal once resistance to Pt therapy (Pt) is observed. To impact this continuing and significant clinical problem, we will exploit the mechanism of Pt-therapy, the induction of DNA damage, in a novel treatment strategy targeting repair of the platinum-DNA lesions. Both cisplatin and carboplatin impart their chemotherapeutic effect by the formation of intrastrand Pt-DNA adducts. These adducts are repaired by the nucleotide excision repair (NER) pathway which relies on the ERCC1/XPF nuclease to excise the Pt-damaged DNA. Pt therapy also generates interstrand Pt-DNA adducts which are thought to be repaired via a DNA double strand break/homologous recombination pathway. This pathway also relies on the ERCC1/XPF nuclease. ERCC1 has been extensively studied in lung cancer with expression inversely correlated with response to Pt therapy in numerous clinical trials providing the clinically and biologically validated rationales for targeting this nuclease. Inhibition of ERCC1/XPF in ERCC1 positive cancers is likely to be highly effective in sensitizing cells to cisplatin while the further reduction of ERCC1/XPF activity in ERCC1 low expression cancers holds the potential for enhanced activity of cisplatin and greater tumor killing to ultimately impact overall survival. While, the effect of XPF/ERCC1 inhibition on normal cells is likely to be minimal in the absence of Pt-treatment, the potential for normal cell toxicity in combination with Pt- therapy does exist. However, the reliance of a large number of cancers on overexpression of ERCC1 and potential synthetic lethal interactions in cancer with other mechanism of genome instability, support the possibility that reduced toxicity will be observed and an increase in the Pt therapeutic window can be achieved. Therefore, we will pursue the optimization and implementation of a high-throughput screen (HTS) to identify specific and potent inhibitors of ERCC1/XPF nuclease activity. Hits will be confirmed in secondary assays and lead molecules selected. Successful completion of these studies will support a phase II SBIR application to pursue lead compound development and assess compound activity in cell culture and animal models of non- small cell lung cancer (NSCLC) for the ability to reduce ERCC1/XPF nuclease activity, enhance cisplatin effectiveness and ultimately increase survival.
The research proposed in this application is directly relevant to public health in that we are developing novel therapies for the treatment of cancer. Successful completion of this work has the potential to impact those individuals diagnosed with cancer that will receive platinum-based therapy. Providing a more effective treatment regimen is essential to increase overall survival and enhance quality of life for those diagnosed with cancer.
